Michiko Asano1, Akiko Sekikawa2, Hyosung Kim3, Robert A Gasser4, Darren Robertson5, Marcella Petrone6, Lutz Jermutus5, Philip Ambery7. 1. Medical Science, BioPharmaceuticals TA, R&D, AstraZeneca K.K., Tokyo, Japan. 2. Clinical Science, BioPharmaceuticals TA, R&D, AstraZeneca K.K., Tokyo, Japan. 3. Biometrics, Science & Data Analytics Division, R&D, AstraZeneca K.K., Osaka, Japan. 4. Microbial Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland, USA. 5. Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), AstraZeneca, Cambridge, UK. 6. Clinical Pharmacology and Quantitative Pharmacology, AstraZeneca, Cambridge, UK. 7. Late-stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Abstract
AIM: To evaluate the safety and pharmacokinetics of cotadutide, a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in overweight Asian participants with or without type 2 diabetes (T2D). MATERIALS AND METHODS: In the phase 1, randomized, blinded, single-ascending dose study, 24 Japanese and eight Chinese healthy adults (body mass index [BMI] 23-40 kg/m2 ) receivedone subcutaneous dose of cotadutide (50-150 or 100 μg, respectively) or placebo. The primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced uptitration, 61 Japanese adults with T2D (BMI 24-40 kg/m2 ; HbA1c 7.0%-10.5%) receivedcotadutide (100, 200, 300 μg) or placebo for 48 days. Co-primary endpoints were safety/tolerability, change in glucose AUC0-4h and body weight. RESULTS: Significant reductions from baseline to day 48 were observed with cotadutide for glucose AUC0-4h (33.6%-42.1% reduction vs. +2.5% with placebo; 95% CIs: 100 μg -45.7%, -33.7%; 200 μg -35.6%, -23.7%; 300 μg -45.0%, -30.8%; placebo 3.4%, 8.3%) and body weight (1.3%-2.5% decrease vs. +0.8% with placebo; 95% CIs: 100 μg -3.4%, -0.8%; 200 μg -4.7%, -2.0%; 300 μg -4.6%, -2.1%; placebo -2.1%, 0.4%). The most common adverse events with cotadutide were mild gastrointestinal symptoms with no serious adverse events. Increased pulse rate with cotadutide versus placebo is consistent with GLP-1 monoagonists. CONCLUSIONS: Once-daily cotadutide was effective and well tolerated up to 300 μg in overweight Japanese patients with T2D. Further evaluation in Asian populations is warranted.
RCT Entities:
AIM: To evaluate the safety and pharmacokinetics of cotadutide, a dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in overweight Asian participants with or without type 2 diabetes (T2D). MATERIALS AND METHODS: In the phase 1, randomized, blinded, single-ascending dose study, 24 Japanese and eight Chinese healthy adults (body mass index [BMI] 23-40 kg/m2 ) received one subcutaneous dose of cotadutide (50-150 or 100 μg, respectively) or placebo. The primary endpoint was safety. In the phase 2a, randomized, double-blinded, parallel dose-ranging study with forced uptitration, 61 Japanese adults with T2D (BMI 24-40 kg/m2 ; HbA1c 7.0%-10.5%) received cotadutide (100, 200, 300 μg) or placebo for 48 days. Co-primary endpoints were safety/tolerability, change in glucose AUC0-4h and body weight. RESULTS: Significant reductions from baseline to day 48 were observed with cotadutide for glucose AUC0-4h (33.6%-42.1% reduction vs. +2.5% with placebo; 95% CIs: 100 μg -45.7%, -33.7%; 200 μg -35.6%, -23.7%; 300 μg -45.0%, -30.8%; placebo 3.4%, 8.3%) and body weight (1.3%-2.5% decrease vs. +0.8% with placebo; 95% CIs: 100 μg -3.4%, -0.8%; 200 μg -4.7%, -2.0%; 300 μg -4.6%, -2.1%; placebo -2.1%, 0.4%). The most common adverse events with cotadutide were mild gastrointestinal symptoms with no serious adverse events. Increased pulse rate with cotadutide versus placebo is consistent with GLP-1 monoagonists. CONCLUSIONS: Once-daily cotadutide was effective and well tolerated up to 300 μg in overweight Japanese patients with T2D. Further evaluation in Asian populations is warranted.